Abstract Malignant Pleural Mesothelioma (MPM) is an aggressive cancer effecting the lining of the lungs and is most often caused by exposure to asbestos. MPM is difficult to detect and is typically diagnosed late resulting in a median survival of just one year and a 5-year median survival of only 5-10%. Pemetrexed (Pmx) is the standard of care but quality of life is poor due to Pmx toxicities. The purpose of this Direct to Phase II SBIR grant application is to examine several novel therapeutic molecules as a treatment for patients with MPM. These molecules are unique as they are designed to be small molecule targeted therapeutics. These FTAC (facilitative transporter anti-cancer) molecules (AGF-series) are potent chemotherapeutics which kill cells by inhibiting GARFTase (glycinamide ribonucleotide formyltransferase), which inhibits purine synthesis and results in cell death. But what differentiates FTAC molecules and makes them uniquely effective, is that FTAC molecules exhibit selective uptake by the PCFT (proton-coupled facilitative transporter). The PCFT is a scavenger system that only exists in cancer cells and thereby offers a mechanism to differentiate a cancer cell from a normal healthy cell for a targeted therapeutics approach. Initial studies have shown FTAC molecules to be 100-fold more selective to cancer cells when compared to standard of care (SOC) chemotherapeutics and comparable or superior in cytotoxicity in early animal studies. As the testing of our FTAC molecules is in its infancy but with very exciting and promising results, we plan to thoroughly examine several FTAC molecules to identify those compounds that show maximal selectivity and efficacy with minimal side effects. MPM was chosen as the initial disease to study as it has very few effective therapeutic treatment options for patients and MPM tissues express high levels of PCFT, which should increase FTAC?s targeting efficiency and produce a superior therapeutic with fewer negative side effects. In order to achieve this goal, the following Specific Aims are proposed: Aim 1: Synthesize and test analogs of AGF-094/-238 for improved potency and PCFT selectivity. Aim 2: Testing of compounds for potency and PCFT selectivity in vitro and in vivo. Aim 3: Testing the efficacy of up to 2 compounds in MPM PDX SCID mice models. Aim 4: Initiation of IND enabling safety and DMPK studies on the top compounds for clinical development To the best of our knowledge, these molecules are the first cytotoxic compounds with selective uptake and therefore have the potential to provide a significant clinical benefit to MPM patients.